1. Field of the Invention
This invention relates to 2-desmethyl ansamycin compounds, methods for their preparation, and their use for treating hyperproliferative diseases, in particular cancer.
2. Description of Related Art
Geldanamycin belongs to the ansamycin family of natural products, whose members are characterized by a benzenoid nucleus (typically a benzoquinone or hydroquinone nucleus) connected at two meta positions to form a macrocyclic lactam. Besides geldanamycin, the ansamycins include the macbecins, the herbimycins, the TAN-420s, and reblastatin:

Geldanamycin and its derivatives are the most extensively studied of the ansamycins. Although geldanamycin was originally identified as a result of screening for antibiotic activity, current interest in it is based primarily on its cytotoxicity towards tumor cells and, therefore, its potential as an anticancer agent. It is an inhibitor of heat shock protein-90 (“Hsp90”), which is involved in the folding, activation and assembly of a wide range of proteins (“client proteins”), including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. The binding of geldanamycin to Hsp90 disrupts Hsp90-client protein interactions, preventing the client proteins from folding correctly and rendering them susceptible to proteasome-mediated destruction. Among the Hsp90client proteins are many mutated or overexpressed proteins implicated in cancer: p53, Bcr-Abl kinase, Raf-1 kinase, Akt kinase, Npm-Alk kinase p185ErB2 transmembrane kinase, Cdk4, Cdk6, Weel (a cell cycle-dependent kinase), HER2/Neu (ErbB2), and hypoxia inducible factor-1α (HIF-1α). However, the hepatotoxicity and poor bioavailability of geldanamycin have lead to its discontinuation as a clinical candidate.
Nevertheless, interest persists in the development of geldanamycin derivatives or analogs (collectively “geldanamycin compounds”) having geldanamycin-like bioactivity, but with a better overall spectrum of properties. Position 17 of geldanamycin has been an attractive focal point, chemically speaking, for the synthesis of geldanamycin compounds because its methoxy group is readily displaced by a nucleophile, providing a convenient entry into 17-substituted-17-desmethoxygeldanamycin compounds. Further, structure-activity relationship (SAR) studies have shown that structurally and sterically diverse 17-substituents can be introduced without destroying antitumor activity. For exemplary disclosures relating to 17-substituted geldanamycin compounds, see Sasaki et al., U.S. Pat. No. 4,261,989 (1981); Schnur et al., U.S. Pat. No. 5,932,566 (1999); Schnur et al., J. Med. Chem., 38, 3806-3812 (1995); Schnur et al., J. Med. Chem., 38,3813-3820 (1995); and Ho et al., WO 00/03737 (2000); the disclosures of which are incorporated by reference. The SAR inferences are supported by the X-ray crystal co-structure of the complex between Hsp90α and a geldanamycin derivative (17-DMAG, v. infra), showing that the 17-substituent projects out from the binding pocket and into the solvent (Jez et al., Chemistry & Biology, 10, 361-368 (2003)). (Hsp90 exists in a number of isoforms, with the α-isoform being the most common one. For a review on Hsp90 isoforms, see Sreedhar et al., FEBS Letters 562 (1-3), 11-15 (2004). Herein, where a particular isoform is referred to, abbreviations such as “Hsp90α” or “Hsp90β” will be used, with “Hsp90” reserved for Hsp90 generically.) Thus, position 17 is a choice one for the introduction of property-modulating substituents, such as a solubilizing group.
The best-known 17-substituted geldanamycin is 17-allylamino-17-demethoxy-geldanamycin (“17-AAG”), currently undergoing clinical trials. Another noteworthy 17-substituted geldanamycin is 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (“17-DMAG”) (Snader et al., WO 02/079167 A1 (2002), incorporated by reference).

The literature relating to ansamycins wherein the aromatic nucleus is other than a benzoquinone group (e.g., at the hydroquinone or phenol oxidation state) is sparse—not an unexpected outcome considering the benzoquinone group's key role in the activation of the 17-OMe group. There are some disclosures on the isolation of non-benzoquinone natural product congeners such as Macbecin II, TAN-420A, TAN-420B, TAN-420E, and reblastatin. Disclosures of semi-synthetic non-benzoquinone ansamycin derivatives include Rinehart, Jr., et al., U.S. Pat. No. 3,987,035 (1976); Muroi et al., U.S. Pat. No. 4,421,688 (1983); Schnur, U.S. Pat. No. 5,387,584 (1995); Cullen et al., WO 93/14215 A1 (1993); and Sasaki et al., JP 57-163369A (1982); the disclosures of which are incorporated by reference.